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Dihydropyrrolones derivative as Caspase-3 inhibitor

A technology of dihydropyrrolidone and its derivatives, which can be used in anti-inflammatory agents, antiviral agents, drug combinations, etc., and can solve problems such as cytotoxicity

Inactive Publication Date: 2013-08-14
SOUTH CHINA UNIV OF TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, due to the problems of cytotoxicity and certain differences between the experimental results in vivo and in vitro, so far only a few Caspase-3 inhibitors are undergoing preclinical trial experiments, such as Merck's M-791

Method used

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  • Dihydropyrrolones derivative as Caspase-3 inhibitor
  • Dihydropyrrolones derivative as Caspase-3 inhibitor
  • Dihydropyrrolones derivative as Caspase-3 inhibitor

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0050] For the synthesis method in Example 1, refer to Method B reported in the literature (J.Comb.Chem.2009,11,685-696): primary aromatic amine (4mmol), 38% formaldehyde (120mg, 1.5mmol) and acetic acid ( 120mg, 2mmol) were sequentially added to the reaction solution (reaction 10-30 minutes) of the primary amine arylamine (1mmol) and butyndioic acid diester (1mmol) with ethanol (4mL) as the solvent, and stirred at 70°C until the reaction was complete (Reaction monitored by TLC). Use 20×20 GF 254 A thin-layer chromatography plate uses a mixed solvent of petroleum ether: ethyl acetate = 10:1-1:1 as a developing solvent, and uses ethyl acetate as an eluent to separate and purify the product.

[0051] For the synthesis method in Examples 2-15, refer to Method A reported in the literature (J.Comb.Chem.2009, 11, 685-696): primary amine (2mmol), 38% formaldehyde (120mg, 1.5mmol) and acetic acid (120mg, 2mmol) was added successively to the reaction solution (reaction of 10-30 minut...

Embodiment 2

[0056] 2,5-Dihydro-1-n-propyl-4-(cyclohexylamino)-5-oxo-1H-pyrrole-3-carboxylic acid ethyl ester (ethyl4-(cyclohexylamino)-2,5-dihydro-5- oxo-1-propyl-1H-pyrrole-3-carboxylate compound number JZP-20 / 749-1). Yellowish solid, 1H NMR (600MHz, CDCl3): δ=6.75(b, 1H), 4.595-4.591(m, 1H), 4.20(q, J=7.2Hz, 2H), 3.93(s, 2H), 3.41 (t, J=7.2Hz, 2H), 1.98-1.96(m, 2H), 1.73-1.67(m, 11H), 0.92(t, J=7.2Hz, 3H) ppm.13C NMR (150MHz, CDCl3): δ = 165.4, 100.0, 59.4, 44.5, 34.9, 25.5, 24.7, 21.5, 14.6, 11.3 ppm. GC-MS: 294 (M+).

Embodiment 3

[0058] 2,5-Dihydro-1-cyclohexyl-4-(cyclohexylamino)-5-oxo-1H-pyrrole-3-carboxylic acid ethyl ester (ethyl1-cyclohexyl-4-(cyclohexylamino)-2,5-dihydro - 5-oxo-1H-pyrrole-3-carboxylate Compound No. JZP-21 / 749-2). White solid; 1H NMR (600MHz, CDCl3): δ=6.62(b, 1H), 4.48(b, 1H), 4.09-4.08(m, 2H), 3.89(b, 1H), 3.80(b, 2H), 1.87-1.28 (m, 10H), 1.19-1.05 (m, 13H) ppm.13CNMR (150MHz, CDCl3): δ=165.6, 164.7, 96.4, 59.2, 51.1, 50.3, 43.4, 34.8, 31.0, 25.5, 25.4, 24.7, 14.5 ppm. GC-MS: 334 (M+).

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Abstract

The invention discloses a Caspase-3 inhibitor, namely a dihydropyrrolones derivative, with a molecular structural formula (1), and pharmaceutically acceptable salts thereof. In the molecular structural formula, R1 represents alkyl, aryl or heterocyclic radical; R2 represents hydrogen, alkyl, aryl or heterocyclic radical; R3 represents alkoxyl, aryloxy, primary amino radical or secondary amino radical; and R4 represents primary amino radical, secondary amino radical, alkoxyl, aryloxy, alkylthio radical, arylthio radical or N-containing heterocyclic radical. The dihydropyrrolones derivative or the pharmaceutically acceptable salts thereof, as a Caspase-3 inhibitor, can be applied to treating diseases caused by excessive apoptosis of cells, such as acquired immunity deficiency syndrome, serious hepatitis, osteoarthritis, senile dementia, Parkinson's disease, amyotrophic lateral sclerosis, Huntingdon's chorea, spinal and cerebellar ataxia, muscular dystrophy, cerebral ischemia, cerebral injury and the like, singly or by combining with other medicines.

Description

technical field [0001] The present invention relates to dihydropyrrolidone derivatives and pharmaceutically acceptable salts thereof, and also relates to the application of dihydropyrrolone derivatives and pharmaceutically acceptable salts thereof in medicine. Background technique [0002] Apoptosis, also known as programmed cell death, is an extremely important physiological process that maintains the normal growth and development and dynamic balance of organisms together with cell proliferation. When apoptosis is insufficient, cancer, viral diseases and autoimmune diseases are prone to occur; while excessive apoptosis may cause acquired immunodeficiency syndrome, severe hepatitis, osteoarthritis and neurodegenerative diseases. The mechanism of regulating apoptosis involves a complex protease cascade reaction process, which includes a variety of regulatory factors, a class of proteases called Caspase (cysteinyl aspartate-specific protease, caspase) in the initiation and exe...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07D401/04C07D207/36A61K31/4439A61K31/4015A61K31/402A61K31/5377A61P25/28A61P1/16A61P25/16A61P31/18A61P19/02A61P29/00A61P25/14A61P21/00A61P9/10A61P25/00
Inventor 江焕峰朱秋华李佳高立信
Owner SOUTH CHINA UNIV OF TECH
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